Alloplastic injectable dermal filler and methods of use thereof

ABSTRACT

A composition comprising an alloplastic injectable suspension for use as a dermal filler comprising a biocompatible and pliable material and a physiologically acceptable suspending agent is provided. A method of making a composition comprising an alloplastic injectable suspension for use as a dermal filler comprising a biocompatible and pliable material and a physiologically acceptable suspending agent, said method comprising admixing a biocompatible and pliable material with a physiologically acceptable suspending agent, is also provided. A method of augmenting soft tissue to provide long-term reduction of a skin defect, said method comprising stimulating collagen beneath the skin defect is further provided. In an embodiment of the method of augmenting soft tissue, the stimulation of collagen production is effected by injecting into the deep reticular dermis an a dermal filler, said dermal filler being an alloplastic injectable suspension and comprising a biocompatible and pliable material and a physiologically acceptable suspending agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is continuation of U.S. Patent Application No.12/741,280, filed Sep. 7, 2010, which is a national stage application ofInternational Patent Application No. PCT/US2008/81608, filed Oct. 29,2008, which is a continuation-in-part of U.S. patent application Ser.No. 11/926,930, filed Oct. 29, 2007, now U.S. Patent No. 7,910,134, thedisclosures of each of which are herein incorporated by reference.

FIELD OF THE INVENTION

This application provides an alloplastic injectable suspension for useas a dermal filler, which produces little or no immunologic response inthe host tissue. This application also provides methods of use of thealloplastic injectable suspension for aesthetic indications, includingwrinkle reduction and medical indications, such as amelioration ofcosmetic defects.

BACKGROUND OF THE INVENTION

Wrinkles of the skin, whether fine superficial lines or deeper creases,are visible signs of aging. Premature aging and its associated wrinklesmay be caused by skin damage from excessive exposure to sunlight andenvironmental pollution, as well as muscle overuse for facial expressionsuch as smiling and frowning. Other factors which may contribute towrinkle formation include smoking tobacco products and exposure tocigarette smoke, poor nutrition and skin disorders.

During the aging process a loss of collagen and hyaluronic acid in theskin occurs resulting in fine wrinkles and creases as well as thinnerskin. Aging-associated wrinkles are known as static wrinkles. Incontrast, dynamic wrinkles are caused by repeated muscle movement whenmaking a facial expressions resulting in skin creases and folds whichremain in the absence of the facial expressions. Dynamic wrinklesinclude smile lines, frown lines, crow's feet, lip wrinkles and foreheadcreases. Sagging of the skin results in the development of wrinkles inthe skin fold. For example, sagging cheeks develop wrinkles in the skinfold known as the nasolabial fold from the corners of the nose, aroundthe sides of mouth and down to the chin.

The quest for youthful-looking skin, free of wrinkles, is centuries old.Treatment of wrinkles due to aging and skin damage must obtain a visibleimprovement in the skin appearance, such as a smoothing effect, for aslong as possible with minimal side-effects, such as immunologicreactions. Treatment of skin defects, whether for cosmetic or medicalreasons must strike a balance between achieving long-term aestheticallypleasing results, minimizing side effects or complications of thetreatment procedure and the host tissue reaction thereto, and decreasingthe recurrence of treatment to achieve the intended results.

Current methods of treatment of wrinkles and sagging skin range from arhytidectomy, commonly known as a face-lift, which involves removingexcess fat, tightening underlying muscles, and redraping the skin of theface and neck to minimally-invasive procedures such as laserresurfacing, chemical peels, and injection of Botulinum toxin type A(BOTOX® (onabotulinumtoxinA)). Each method may not achieve the desiredamelioration of a particular skin defect or only achieve a short-livedimprovement, which necessitates additional treatment with the samecomposition or procedure or the use of a different procedure.

Injectable dermal fillers provide a noninvasive option for reducing skindefects, such as wrinkles or scars, with less recovery time than aface-lift. Injectable soft-tissue fillers raise the skin within the skindefect, which is lower or deeper than the surrounding and upon whichlight casts a shadow to produce a visible sign, such as the defect. Thefilling of soft tissue underneath the skin defect raises of the skinbringing the defect to approximately the same level as the surroundingskin to decrease the shadow.

Collagen, a naturally occurring protein which supports the skin, tendonsand ligaments, has been used as a soft-tissue filler since the early1980s for correcting contour deformities of the dermis in non-weightbearing areas. A common injectable collagen dermal filler, or implant,approved by the U.S. Food and Drug Administration (FDA), is made byextracting bovine collagen from bovine skin, which is purified andsterilized and then dispersed in a phosphate-buffered physiologicalsaline, which contains 3% lidocaine. The collagen may be lightlycross-linked with glutaraldehyde or non-crosslinked collagen fillers.These types of fillers have been used to improve distensible acne scars,atrophy caused by disease or trauma, glabellar frown lines, nasolabialfolds, rhinoplasty, skin graft or other surgically-inducedirregularities and soft tissue defects. Prior patient skin testing isrequired to determine the existence of an allergy to collagen. Bovinecollagen injections produce immediate results, but its amelioration ofskin defects are transient, lasting only from six weeks up to sixmonths, and also pose a risk of allergic reactions and potentialconnective tissue disorders.

Other collagen dermal fillers are available. Autologen is a collagenextracted from the patient's own skin, sterilized and processed intoinjectable form and the effects of its injection appear to last longerthan bovine collagen injections, but are variable. Isolagen, is apreparation of live cloned fibroblasts, such as collagen-producingcells, which are also derived from a patient's own skin and preparedinto liquid form. These live fibroblasts may improve skin defects overseveral months, but three injections at two- week intervals arerecommended for a higher percentage of wrinkle improvement andmaintenance injections may be needed. Dermalogen, is sterilized,purified and processed collagen obtained from deceased human donors.This collagen filler also may last longer than bovine collages andminimize the risk of allergic reactions and connective tissue disorders,but theoretical risk of infection transmission exists. This treatment ofskin defects may require additional injections and its effects mayreduce over time.

Hyaluronic acid, another skin component, also is used as a dermalfiller. Animal-derived, for example, extracted from rooster combs, andnon-animal hyaluronic acid skin fillers, for example, recombinantlyproduced hyaluronic acid or synthetically produced hyaluronic acid, areavailable commercially for treatment of moderate to severe (deep) facialwrinkles and folds and for adding volume around the nose and mouth andother soft tissue. Allergic reaction may occur from an injection of ananimal-derived hyaluronic acid or dermal fillers in patients sensitiveto avian products, as well as with the recombinantly produced hyaluronicacid in those with allergies to bacterial proteins. Although immediatecorrection of wrinkles and folds is achieved after injection of thesehyaluronic acid soft-tissue fillers, their effects are temporary,lasting from up to six months to up to a year.

Calcium hydroxyapatite, a component of bone and teeth, is also used inan injectable dermal filler in the form of microspheres suspended in anaqueous carrier. Unlike with the above-described skin fillers, the hosttissue reacts to the injected calcium hydroxyapatite microspheres tostimulate collagen production to encapsulate each foreign microsphereindependently, thereby adding bulk (volume) under the skin defect toreduce its appearance. Calcium hydroxyapatite microsphere injectabledermal filler is approved for treatment of moderate to severe (deep)wrinkles and folds. The results of an injection of a suspension ofcalcium hydroxyapatite microspheres are reported to be immediate andlonger lasting than the effects of collagen skin filler, such as fromabout one to two years.

Synthetic poly-lactic acid, which is biodegradable and biocompatible, iscontained in microspheres in another fairly recent injectable dermalfiller approved outside the United States for the correction of finelines, wrinkles, furrow and creases. In the United States, thisinjectable poly-lactic acid microsphere skin filler is FDA approved forrestoration and/or correction of lipoatrophy in HIV patients. Thepoly-lactic acid microspheres having a diameter of 2 to 50 μm in thedermal filler become porous after a first phase of moderate inflammationin the host tissue, followed by a second stronger inflammation in whichforeign body giant cells phagocytose the microspheres and speed up theimplant's degradation. The improvement of skin defects is immediate andhas been reported to endure for up to two years. The non-resorbablemicrospheres add permanent volume under the treated skin defect, as wellas stimulate the host to produce collagen fibers around the implant.Potential adverse side effects of injected poly-lactic acid micro sphereskin filler include the formation of an inflammatory granuloma and lumpformation.

Another permanent microsphere-based injectable dermal filler containslarger non-resorbable microspheres made of polymethyl methacrylate(PMMA), each having a diameter of between 30 and 42 μm and a smoothsurface, and a highly purified bovine collagen gel in a ratio of 20%PMMA to 80% bovine collagen. This injectable dermal filler also contains0.3% lidocaine anesthetic solution. The diameter of solid particles maybe larger, see e.g., U.S. Pat. No. 5,344,452, which is incorporatedherein by reference in its entirety. Because of the collagen content ofthis injectable dermal filler, a skin test for collagen allergy isrequired. The injectable PMMA-bovine dermal filler is FDA approved as anon-resorbable aesthetic injectable implant for correction of nasolabialfolds, such as smile lines. It is injected into deep dermis, hypodermisor epiperiosteally, but is difficult to use in the lips as musclemovement compress the microspheres injected in a row, or strand, to formnodules. Although immediate wrinkle improvement results from thisparticular injectable dermal filler, two to three additional treatmentsabout four to eight weeks apart may be required to achieve the finaldesired result. Adverse side-effects include lumpiness and inflammatorygranulomas. Treatment with injectable PMMA-collagen dermal filler iscontraindicated in patients with known bovine allergies and lidocaineallergies, as well as those with susceptibility to keloid formation.Treatment with this dermal filler is considered permanent, not onlybecause of the volume increase under the skin defect, but also becauseof the presumed life-long stimulation of collagen deposition beneath theskin defect.

The electrical charge of dermal filler microbeads appears to play a rolein attracting and activating macrophages, which promotes formation offoreign body giant cells, then fibroblasts, and thereby increases thecomposition of new connective tissue.

Each of these methods of treatment for skin defects, such as wrinkles,scars or other deformities, provides a varying duration of effect inreducing the skin defect or stimulating host production of fibroblastsand fibrocytes, produces an immediate and/or delayed immune response,poses a risk of allergy and results in palpable or visible side-effects,such as clumping, lumping, nodule formation and granuloma formation.

Accordingly, there still exists an unmet need for compositions forlong-term reduction of skin defects associated with the aging process orpremature aging, such as dynamic wrinkles, static wrinkles, finewrinkles, acne scars, surgery scars, injury scars. It is desirable thatthe such compositions produce a smoothing of the skin without causing anallergic reaction, an immediate inflammatory response, a delayedinflammatory response or a recurring inflammatory response in the hosttissue. Also desirable are methods of producing compositions forlong-term reduction of skin defects, as well as methods of using suchcompositions to augment soft tissue by inducing in the host tissuestimulation of collagen production fibroblast production, fibrocyteproduction or production of any combination thereof.

SUMMARY

A composition comprising an alloplastic injectable suspension for use asa dermal filler comprising a biocompatible and pliable material and aphysiologically acceptable suspending agent is provided in anembodiment.

A method of making a composition comprising an alloplastic injectablesuspension for use as a dermal filler comprising a biocompatible andpliable material and a physiologically acceptable suspending agent, saidmethod comprising admixing a biocompatible and pliable material with aphysiologically acceptable suspending agent, is also provided in anotherembodiment.

A method of augmenting soft tissue to provide long-term reduction of askin defect, said method comprising stimulating collagen production,fibroblast production, fibrocyte production or production of anycombination thereof, beneath the skin defect, is further provided in anembodiment.

A method of reducing wrinkles and scars, said method comprisingstimulating collagen production, fibroblast production, fibrocyteproduction or production of any combination thereof, beneath the skindefect, is further provided in an embodiment.

In an embodiment of the methods of augmenting soft tissue and reducingwrinkles and scars, the stimulation of collagen production fibroblastproduction, fibrocyte production or production of any combinationthereof is effected by injecting into the superficial dermis, deepdermis, hypodermis, subcutaneous tissue or epiperiosteally (near andabove a bone) a dermal filler, said dermal filler being an alloplasticinjectable suspension and comprising a biocompatible and pliablematerial and a physiologically acceptable suspending agent

These and other embodiments will become readily apparent to thoseskilled in the art upon review of the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of promoting an understanding of the embodimentsdescribed herein, reference will be made to embodiments and specificlanguage will be used to describe the same. The terminology used hereinis for the purpose of describing particular embodiments only, and is notintended to limit the scope of the present invention. As used throughoutthis disclosure, the singular forms “a,” “an,” and “the” include pluralreference unless the context clearly dictates otherwise. Thus, forexample, a reference to “a composition” includes a plurality of suchcompositions, as well as a single composition.

A “copolymer” is a polymer comprising more than one monomer in thepolymer chain.

An “acrylate/methacrylate copolymer” is defined herein as the copolymerused in AcrySof MA60BM intraocular lenses (Alcon Laboratories) and forother uses such as fabrication of porous membranes, as well as inpharmaceuticals. These copolymers are inert in nature and have a myriadof uses in numerous industries.

A composition comprising an alloplastic injectable suspension for use asa dermal filler comprising a biocompatible and pliable material and aphysiologically acceptable suspending agent is provided in anembodiment.

In an embodiment, the biocompatible and pliable material is a copolymerof an unsubstituted acrylate monomer and a substituted acrylate monomer.

In a further embodiment of this copolymer, the substituted acrylatemonomer is substituted with a methyl group. The copolymer of anunsubstituted acrylate monomer and a substituted acrylate monomer is notabsorbable or degradable by the body and is inert, and unrecognized bythe immune system. The immunologic inertness of the copolymer does notallow for formation of inflammatory granuloma and scarring. Thecopolymer of an unsubstituted acrylate monomer and a substitutedacrylate monomer is pliable, a characteristic that is important for skinapplications. The copolymer material also is hydrophobic, which may bebeneficial for expansion of the skin in areas where wrinkles form. Thecopolymer of an unsubstituted acrylate monomer and a substitutedacrylate monomer may have a tint for easier removal, if needed, such asin cases of a face lift after injection of material years later.

In another embodiment of the copolymer of an unsubstituted acrylatemonomer and a substituted acrylate monomer, the substituted acrylatemonomer may be substituted with a functional group other than a methylgroup. Substituent groups may include those groups that are unreactive(or a potentially reactive group, which is rendered inaccessible toreaction) and of the same or equivalent steric size as a methyl group.However, the steric size of a substituent group is not limited to onesimilar to a methyl group. For example, other alkyl group derivativesmay impart the same type of pliability property, e.g., one to four (evenfive) carbon chain lengths (methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl) acrylate derivatives. Such derivatives also arewidely available commercially. An alternative substituent group for thesubstituted acrylate monomer may be chlorine, which takes up about thesame steric space as a methyl group. Chlorine may be a reactive group,but its potential reactivity may not interfere with its use as asubstituent group for the substituted acrylate monomer because the solidnon-dispersed state of the copolymer would render the chlorine groupinaccessible, i.e., hidden from reaction with another reactive group.Nitrile groups are another possible substituent for the substitutedacrylate monomer, as they also may be similar in size to a methyl group.A nitrile group potentially may be reactive, however this potentialreactivity may not impede its use as a substituent for the same reasonsas described for the chlorine group. Other halogens may be suitable foruse in substitution of the substituted acrylate monomer, as well.Substitution of the substituted acrylate monomer with a phenyl group mayalso impart pliability to the copolymer. A phenyl substituent may beused if no pi- stacking of the phenyl groups occurs, i.e., stacking ontop of each other.

In another embodiment of the composition comprising an alloplasticinjectable suspension, the biocompatible and pliable material is anacrylate/methacrylate copolymer.

In a further embodiment of the composition comprising an alloplasticinjectable suspension, the acrylate/methacrylate copolymer is a solid.In an embodiment, the solid may be a non-porous microbead. In a stillfurther embodiment, the solid may be a powder. In another embodiment,the solid may be a microsphere. In a further embodiment of thealloplastic injectable suspension, the solid has a diameter of about 10μto about 100μ.

In accordance with various embodiments of the present invention, theacrylate/methacrylate copolymer is in the form of particles each havinga diameter of less than about 100μ. According to a preferred embodiment,the diameter of each particle is less than about 10μ. In accordance withanother preferred embodiment, the particles each have a diameter ofabout 0.01μ to about 10μ. In another preferred embodiment, the particleseach have a diameter of about 0.1μ to about 5μ.

In an embodiment of the alloplastic injectable suspension, thephysiologically acceptable suspending agent is resorbable, such as it isabsorbed by the body, but not degraded.

The physiologically acceptable suspending agent may be a bufferedphysiological solution in another embodiment of the alloplasticinjectable suspension. In an alternative embodiment, the physiologicallyacceptable suspending agent comprises cross-linked sodium hyaluronate.In a further alternative embodiment, the physiologically acceptablesuspending agent comprises a non cross-linked sodium hyaluronate. Inembodiments wherein the buffered physiological solution comprises noncross-linked or cross-linked sodium hyaluronate as a suspending agent,the sodium hyaluronate may comprise from about 10% to about 80% of thebuffered physiological solution.

In yet another embodiment of the composition comprising an alloplasticinjectable suspension, the physiologically acceptable suspending agentcomprises collagen. In a further embodiment, the collagen is derivedfrom an animal. In a still further embodiment, the collagen is derivedfrom a bird.

In another embodiment of the composition comprising an alloplasticinjectable suspension, the collagen is genetically engineered inbacteria. In an embodiment, the bacteria may be any bacteria used forrecombinant expression of proteins. The bacteria may be a Streptococcusstrain in a further embodiment.

A method of making a composition comprising an alloplastic injectablesuspension for use as a dermal filler comprising a biocompatible andpliable material and a physiologically acceptable suspending agent, saidmethod comprising admixing a biocompatible and pliable material with aphysiologically acceptable suspending agent is provided in anembodiment.

In an embodiment of this method, the biocompatible and pliable materialis a copolymer of an unsubstituted acrylate monomer and a substitutedacrylate monomer.

In a further embodiment of this method, the substituted acrylate monomeris substituted with a methyl group. In other embodiments of thecopolymer of the unsubstituted acrylate monomer and the substitutedacrylate monomer, the substituted acrylate monomer may be substitutedwith a functional group other than a methyl group. Substituent groupsmay include those groups that are unreactive (or potentially reactivegroup, but rendered inaccessible to reaction) and of the same orequivalent steric size as a methyl group, but the steric size of asubstituent group may not be not limited to one similar to a methylgroup. For example, other alkyl group derivatives, e.g., one to four,even five, carbon chain lengths (methyl, ethyl, propyl, isopropyl,butyl, tert-butyl and pentyl) acrylate derivatives, may be used as asubstituent in place of a methyl group of the substituted acrylatemonomer. In an alternative embodiment of the copolymer of anunsubstituted acrylate monomer and a substituted acrylate monomer, asubstituent group for the substituted acrylate monomer may be chlorineor another halogen. A nitrile group may be another possible substituentfor the substituted acrylate monomer. The substituted acrylate monomermay be substituted with a phenyl group, as described above.

In another embodiment of the method of making a composition comprisingan alloplastic injectable suspension for use as a dermal filler, thebiocompatible and pliable material is an acrylate/methacrylatecopolymer. In a further embodiment of this method, theacrylate/methacrylate copolymer is a solid. In yet another embodiment,the solid acrylate/methacrylate copolymer may be a powder. In stillanother embodiment of this method, the solid may be a non-porousmicrobead. In another embodiment of this method, the solid may be amicrosphere. In a further embodiment of the method of making analloplastic injectable suspension for use as a dermal filler, the solidmay have a diameter of about 10μ to about 100μ. According to anotherembodiment, the solid has a diameter of between about 0.01μ to about10μ. In another embodiment, the solid has a diameter of between about0.1μ to about 5μ.

In another embodiment of this method, the physiologically acceptablesuspending agent is resorbable. In an embodiment, the physiologicallyacceptable suspending agent may be a buffered physiological solution. Inyet another embodiment of this method, the physiologically acceptablesuspending agent comprises cross-linked sodium hyaluronate. In anotherembodiment, the physiologically acceptable suspending agent comprises anon cross-linked sodium hyaluronate. In a further embodiment, thephysiologically acceptable suspending agent comprises collagen. In analternative embodiment, the collagen may be derived from an animal. Inanother alternative embodiment of this method, the collagen may bederived from a bird. In a still further embodiment of this method, thecollagen may be genetically engineered in bacteria. In an embodiment,the bacteria may be any bacteria used for recombinant expression ofproteins. The bacteria may be a Streptococcus strain in a furtherembodiment.

A method of augmenting soft tissue to provide long-term reduction of askin defect, said method comprising stimulating collagen production,fibroblast production, fibrocyte production or production of anycombination thereof, beneath the skin defect, is provided in anembodiment.

In further embodiment of this method of augmenting soft tissue toprovide long-term reduction of a skin defect, the stimulation ofcollagen production fibroblast production, fibrocyte production orproduction of any combination thereof is effected by injecting into thedeep reticular dermis a dermal filler, said dermal filler being acomposition comprising an alloplastic injectable suspension andcomprising a biocompatible and pliable material and a physiologicallyacceptable suspending agent.

In an embodiment of this method of augmenting soft tissue to providelong-term reduction of a skin defect, the biocompatible and pliablematerial is a copolymer of an unsubstituted acrylate monomer and asubstituted acrylate monomer.

In a further embodiment of this method, the substituted acrylate monomeris substituted with a methyl group. In another embodiment of thecopolymer of the unsubstituted acrylate monomer and the substitutedacrylate monomer, the substituted acrylate monomer may be substitutedwith a functional group other than a methyl group. Substituent groupsmay include those groups that are unreactive (or potentially reactivegroup, which are rendered inaccessible to reaction) and of the same orequivalent steric size as a methyl group, but the steric size of asubstituent group may not be not limited to one similar to a methylgroup. For example, other alkyl group derivatives, e.g., one to four,even five, carbon chain lengths (methyl, ethyl, propyl, isopropyl,butyl, tert-butyl and pentyl)acrylate derivatives, may be used as asubstituent in place of a methyl group of the substituted acrylatemonomer. In an alternative embodiment of the copolymer of anunsubstituted acrylate monomer and a substituted acrylate monomer, asubstituent group for the substituted acrylate monomer may be chlorineor another halogen. A nitrile group may be another possible substituentfor the substituted acrylate monomer. The substituted acrylate monomermay be substituted with a phenyl group, as described above.

In another embodiment of the method of augmenting soft tissue to providelong-term reduction of a skin defect, the biocompatible and pliablematerial is an acrylate/methacrylate copolymer. In a further embodimentof this method, the acrylate/methacrylate copolymer is a solid. In yetanother embodiment, the solid acrylate/methacrylate copolymer may be apowder. In still another embodiment of this method, the solid may be anon-porous microbead. In another embodiment of this method, the solidmay be a microsphere. In a further embodiment of the method ofaugmenting soft tissue to provide long-term reduction of a skin defect,the solid may have a diameter of about 10μ to about 100μ.

According to further embodiments of the method for augmenting softtissue to provide long-term reduction of a skin defect, theacrylate/methacrylate is in the form of finely ground solid particleshaving a diameter of less than about 100μ. According to an embodiment,the diameter of the finely ground solid particles is less than about10μ. According to a preferred embodiment, the particles have a diameterof about 0.01μ to about 10μ. According to another preferred embodiment,the particles have a diameter of about 0.1μ to about 5μ.

In another embodiment of this method, the physiologically acceptablesuspending agent is resorbable. In an embodiment, the physiologicallyacceptable suspending agent may be a buffered physiological solution. Inyet another embodiment of this method, the physiologically acceptablesuspending agent comprises cross-linked sodium hyaluronate. In anotherembodiment, the physiologically acceptable suspending agent comprises anon cross-linked sodium hyaluronate. In a further embodiment, thephysiologically acceptable suspending agent comprises collagen. In analternative embodiment, the collagen may be derived from an animal. Inanother alternative embodiment of this method, the collagen may bederived from a bird. In a still further embodiment of this method, thecollagen may be genetically engineered in bacteria. In an embodiment,the bacteria may be any bacteria used for recombinant expression ofproteins. The bacteria may be a Streptococcus strain in a furtherembodiment

The dermal filler may be injected below the skin defect at a junction ofthe dermis and subcutaneous fat in an embodiment of this methodaugmenting soft tissue to provide long-term reduction of a skin defect.In another embodiment, the injected dermal filler produces littleimmunologic response in the host tissue or no immunologic response inthe host tissue. In a further embodiment, the skin defect may be aresult of loss of collagen and hyaluronic acid in the skin during theaging process. In an alternative embodiment, the skin defect may be aresult of premature aging, said premature aging caused by overexposureto sunlight, overexposure to environmental pollutants, smoking tobaccoproducts, exposure to cigarette smoke, poor nutrition and skindisorders.

In another embodiment of the method of augmenting soft tissue to providelong-term reduction of a skin defect, the skin defect may be a dynamicwrinkle, a fine wrinkles or a static wrinkle. In further alternativeembodiments, the dynamic wrinkle may be a forehead crease, a brow burrowor an eye line (crow's feet). In a still further alternative embodiment,the static wrinkle may be a skin fold wrinkle resulting from saggingskin. In another embodiment, the skin defect is a medical conditionselected from the group consisting of an acne scar, for example, a“rolling” scar, a “boxcar” scar or an “ice pick” scar, a surgical scar,trauma scar, a large pore and a soft tissue contour defect. In anembodiment, the medical condition is a deformity that requiresre-contouring, such as a small tissue defect (e.g., after animalbite(s)) or a deformity related to trauma where the deformity iscosmetically unappealing. In a further embodiment of the method ofaugmenting soft tissue, the augmentation may be after plastic surgery toachieve symmetry or a desired result

In a further embodiment of the method of augmenting soft tissue toprovide long-term reduction of a skin defect, a “long-term” reduction ofa skin defect is of a duration of at least one year. In anotherembodiment of this method, a long-term reduction of a skin defect is ofa duration of from at least one year to about five years. In stillanother embodiment of this method, a long-term reduction of a skindefect is of a duration from about five years to about ten years. In yetanother embodiment of this method, a long- term reduction of a skindefect is of a duration from about ten years or longer.

A method of reducing wrinkles and scars, said method comprisingstimulating collagen production, fibroblast production, fibrocyteproduction or production of any combination thereof, beneath the skindefect, is further provided in another embodiment.

In an embodiment of this method of reducing wrinkles and scars, thebiocompatible and pliable material is a copolymer of an unsubstitutedacrylate monomer and a substituted acrylate monomer.

In a further embodiment of this method, the substituted acrylate monomeris substituted with a methyl group. In another embodiment of thecopolymer of the unsubstituted acrylate monomer and the substitutedacrylate monomer, the substituted acrylate monomer may be substitutedwith a functional group other than a methyl group. Substituent groupsmay include those groups that are unreactive (or potentially reactivegroup, but rendered inaccessible to reaction) and of the same orequivalent steric size as a methyl group, but the steric size of asubstituent group may not be not limited to one similar to a methylgroup. For example, other alkyl group derivatives, e.g., one to four,even five, carbon chain lengths (methyl, ethyl, propyl, isopropyl,butyl, tert-butyl and pentyl) acrylate derivatives, may be used as asubstituent in place of a methyl group of the substituted acrylatemonomer. In an alternative embodiment of the copolymer of anunsubstituted acrylate monomer and a substituted acrylate monomer, asubstituent group for the substituted acrylate monomer may be chlorineor another halogen. A nitrile group may be another possible substituentfor the substituted acrylate monomer. The substituted acrylate monomermay be substituted with a phenyl group, e.g., where no pi- stacking ofthe phenyl groups occurs.

In another embodiment of the method for reducing wrinkles and scars, thebiocompatible and pliable material is an acrylate/methacrylatecopolymer. In a further embodiment of this method, theacrylate/methacrylate copolymer is a solid. In yet another embodiment,the solid acrylate/methacrylate copolymer may be a powder. In stillanother embodiment of this method, the solid may be a non-porousmicrobead. In another embodiment of this method, the solid may be amicrosphere. In a further embodiment of the method of reducing wrinklesand scars, the solid may have a diameter of about 10μ to about 100μ.

In accordance with further embodiment of the methods of the presentinvention, the acrylate/methaccrylate copolymer is finely milled intoparticles each having less than about 100 μm. In another embodiment, theparticles each have a diameter of less than about 10 μm. In anotherembodiment, the particles each have a diameter of about 0.01 μm to about10 μm. In yet another embodiment, the particles each have a diameter ofabout 0.1 μm to about 5 μm. Based upon the guidance provided herein, aperson skilled in the art would be able to prepare the finely milledcopolymer in accordance with embodiments of the present invention usingreadily available techniques and equipment. For example, withoutlimitation, mills that could be used to mill the copolymer in accordancewith embodiments of the present invention include those manufactured byFritsch.

In another embodiment of this method, the physiologically acceptablesuspending agent is resorbable. In an embodiment, the physiologicallyacceptable suspending agent may be a buffered physiological solution. Inyet another embodiment of this method, the physiologically acceptablesuspending agent comprises cross-linked sodium hyaluronate. In anotherembodiment, the physiologically acceptable suspending agent comprises anon cross-linked sodium hyaluronate. In a further embodiment, thephysiologically acceptable suspending agent comprises collagen. In analternative embodiment, the collagen may be derived from an animal. Inanother alternative embodiment of this method, the collagen may bederived from a bird. In a still further embodiment of this method, thecollagen may be genetically engineered in bacteria. In an embodiment,the bacteria may be any bacteria used for recombinant expression ofproteins. The bacteria may be a Streptococcus strain in a furtherembodiment.

In further embodiment of this method of reducing wrinkles and scars, thestimulation of collagen production fibroblast production, fibrocyteproduction or production of any combination thereof is effected byinjecting into the deep reticular dermis a dermal filler, said dermalfiller being an alloplastic injectable suspension and comprising abiocompatible and pliable material and a physiologically acceptablesuspending agent.

In another embodiment of the method of reducing wrinkles or scars, thedermal filler may be injected below the skin defect at a junction of thedermis and subcutaneous fat to provide a long-term reduction of thewrinkle or scar. In another embodiment of this method, the injecteddermal filler produces little immunologic response in the host tissue orno immunologic response in the host tissue. In a further embodiment, thewrinkle or scar may be a result of loss of collagen and hyaluronic acidin the skin during the aging process. In an alternative embodiment, thewrinkle or scar may be a result of premature aging, said premature agingcaused by overexposure to sunlight, overexposure to environmentalpollutants, smoking tobacco products, exposure to cigarette smoke, poornutrition and skin disorders.

In another embodiment of the method of reducing wrinkles or scars toprovide long-term reduction of the wrinkle or scar, the wrinkle or scarmay be a dynamic wrinkle, a fine wrinkles or a static wrinkle. Infurther alternative embodiments, the dynamic wrinkle may be a foreheadcrease, a brow burrow or an eye line (crow's feet). In a still furtheralternative embodiment, the static wrinkle may be a skin fold wrinkleresulting from sagging skin. In another embodiment, the wrinkle or scaris a medical condition selected from the group consisting of an acnescar, for example, a “rolling” scar, a “boxcar” scar or an “ice pick”scar, a surgical scar, trauma scar, a large pore and a soft tissuecontour defect. In an embodiment, the medical condition is a deformitythat requires re-contouring, such as a small tissue defect (e.g., afteranimal bite(s)) or a deformity related to trauma where the deformity iscosmetically unappealing. In a further embodiment of the method ofreducing wrinkles or scars, the reduction of wrinkles or scars may beafter plastic surgery to achieve symmetry or a desired result

In a further embodiment of the method of reducing wrinkles or scars toprovide long-term reduction of the wrinkle or scar, a “long-term”reduction of a the wrinkle or scar may be of a duration of at least oneyear. In another embodiment of this method, a long-term reduction of athe wrinkle or scar may be of a duration of from at least one year toabout five years. In still another embodiment of this method, along-term reduction of a the wrinkle or scar may be of a duration fromabout five years to about ten years. In yet another embodiment of thismethod, a long-term reduction of a the wrinkle or scar may be of aduration from about ten years or longer.

In accordance with further embodiments of the present invention, thepresent invention contemplates the use of any of the compositionsdescribed herein with other suitable compositions, including as mixturesor as separately administered substances, as would be recognized bypersons skilled in the art based upon the guidance provided herein.According to further embodiments, the present invention contemplates theuse of the compositions as medical devices or in conjunction withsuitable medical devices, including implantable and non-implantablemedical devices and the like, as would be understood by persons skilledin the art.

The following examples are illustrative, but not limiting, of thecompositions and of the present invention. Other suitable modificationsand adaptations as would be known to those skilled in the art, basedupon the guidance provided herein, are within the spirit and scope ofthe embodiments.

EXAMPLE 1 Reduction of Horizontal Forehead Lines

Twenty patients presenting with deep horizontal forehead lines, creasesor wrinkles are treated with injections of alloplastic injectablesuspension for use as a dermal filler comprising acrylate/methacrylate(A/M) copolymer powder (or non-porous microbeads or microspheres) and across-linked sodium hyaluronate, (or non-crosslinked sodiumhyaluronate).

Light topical anesthetic is applied to the skin proximal to thehorizontal forehead lines, creases or wrinkles to alleviate anydiscomfort during injection. A 30-, 27- or 26-gauge needle of a 0.5-inchlength is used. The syringe contains 0.5 cc of the suspended A/Mcopolymer. Needle patency is verified by gently squeezing some of thesuspended A/M copolymer out of the needle tip. The needle is insertedinto the skin beneath and along the line of the forehead line, crease orwrinkle, with constant thumb pressure applied on the syringe. Theinjection is places deep intradermally into the reticular dermis justabove the junction between the dermis and the subcutaneous fat.Resistance from the dermis will be experienced, however, if the needleis placed too deep, there will be little resistance from the fattytissue.

Injection occurs in a tunneling technique, wherein the needle is movedback and forth horizontally just beneath the forehead line, crease orwrinkle, such that the injection occurs simultaneously with withdrawalof the needle. The gray needle should not show through the skin of theline. If injected superficially intradermally, the microbeads ormicrospheres will form small granules in a line akin to a strand ofpearls within the line.

Evenly massage with a fingertip the injected and apply slight pressureto smooth out any detected lumps. Vigorous massage is not advisable, asit will spread the injected suspended A/M copolymer deeper into thetissue and result in loss of the intended effect.

In about three months, the diminished thickness of the dermis recoversits previous thickness. The thickness recovery may be determined mostlythrough the use of before and after photos, thus, the time period mayvary from patient to patient.

A second injection of the suspended A/M copolymer may be placed on topof the first injection layer after a period of four weeks to fourmonths. This additive effect may be used to achieve the desired result.Deeper forehead lines may require a second, third and fourth injectionof the suspended A/M copolymer.

An amount of 0.5 cc of the suspended A/M copolymer will suffice forinjection beneath a forehead line, crease or wrinkle, for example, afrontal furrow. A second injection, if needed, for example, to even thedistribution of the first injected and implanted microbeads ormicrospheres, will inject about the same amount of the suspended A/Mcopolymer, or less, depending on the tissue response and the patient'sdesired result.

Side-effects of superficial injection are treated with corticosteroidcream or intradermal corticosteroid injections. Dermabrasion will removeintradermal granules of microbeads or microspheres. Because of the inertnature of the copolymer, it is not expected to form granules in powderform. If microbeads or microspheres are used, the microbeads ormicrospheres can be spread around through massage within a day or twoafter the injection to even the distribution. Therefore, clumping is notexpected, since it results if there is an inflammatory reaction whichaggregates the copolymer microbeads or microspheres together.

Within four weeks to four months of the last injection of the suspendedA/M copolymer the skin comprising the forehead line, crease or wrinklewill be raised to the same level as the surrounding skin, such that theappearance of the forehead line, crease or wrinkle will be diminished oreliminated. The decrease of appearance or removal forehead line, creaseor wrinkle is expected to be permanent, such as to last at least 18months with no palpability or visibility, and from about five to aboutten years. Muscle movement over a time period of from about five toabout ten years may cause the injected A/M copolymer to deepen by 1/10of a millimeter. If a line, crease or wrinkle appears during this time,an injection of the suspended A/M copolymer is placed on top of theoriginal (or last, if more than one were injected) injection of powder,microbeads or microspheres.

EXAMPLE 2 Reduction of Glabellar Frown Lines

Glabellar frown lines form between the eyebrows in an almost verticalposition proximal to each eyebrow. To test the decrease of theappearance of glabellar frown lines or eliminate them, twenty patientspresenting with moderate or deep frown lines between the eyebrows aretreated with an injection of alloplastic injectable suspension for useas a dermal filler comprising acrylate/methacrylate (A/M) copolymerpowder (or non-porous microbeads or microspheres) and a bufferedphysiological solution (or cross-linked sodium hyaluronate,non-crosslinked sodium hyaluronate or collagen), as the site of theglabellar frown lines in accordance with the procedure described inExample 1.

An injection of 0.5 cc of the suspended A/M copolymer will suffice totreat both glabellar frown lines. The dermis is generally thick and theconnective tissue beneath the glabellar frown lines provides goodsupport for the injected suspended A/M copolymer. The injection shouldnot be placed too far caudally, such as not at the lower or tail end ofthe respective glabellar frown line, as a lump may form. If deep linesexist at the glabellar frown lines, treatment is repeated, as describedabove. A thicker dermis beneath the glabellar frown line permitsintradermal injection without the above-described side-effects.

Within four weeks to four months of the last injection of the suspendedA/M copolymer the skin comprising glabellar frown line will be raised tothe same level as the surrounding skin, such that the appearance of thepreviously existing glabellar frown lines will be diminished oreliminated. The decrease of appearance or removal of glabellar frownlines is expected to be permanent, such as to last at least 18 monthswith no palpability or visibility, and from about five to about tenyears. Muscle movement over a time period of from about five to aboutten years may cause the injected A/M copolymer to deepen by 1/10 of amillimeter. If a glabellar frown line appears during this time, aninjection of the suspended A/M copolymer is placed on top of theoriginal (or last, if more than one were injected) injection of powder,microbeads or microspheres.

EXAMPLE 3 Reduction of Nasolabial Folds

Nasolabial folds, or smile lines, extend from the corners of the nose,around the sides of mouth and down to the chin. To test the decrease ofthe appearance of nasolabial folds or eliminate them, twenty patientspresenting with moderate to deep nasolabial folds are treated byinjection of alloplastic injectable suspension for use as a dermalfiller comprising acrylate/methacrylate (A/M) copolymer powder (ornon-porous microbeads or microspheres) and a buffered physiologicalsolution (or cross-linked sodium hyaluronate, non-crosslinked sodiumhyaluronate or collagen), as the site of the nasolabial folds inaccordance with the procedure described in Example 1, except that theinjections are administered parallel and medially (at the middle) to therespective fold. During the first three days, the injected A/Msuspension may be moved laterally (to the side) by movement of thefacial muscles. Accordingly, the injection is administered directlybeneath and 1-2 mm medially to the crease.

In patients with thin skin, the injection of the suspended A/M copolymermust not be too superficial. Otherwise, side-effects such as erythema,such as reddening, will develop at the injection site and the A/Mmicrobeads or microspheres will be visible as granules.

An injection of 0.5 cc of the suspended A/M copolymer will suffice totreat one nasolabial fold. Therefore, treatment of both nasolabial foldswill require two syringes, each with 0.5 cc the suspended A/M copolymer.Nasolabial folds generally will require a second treatment with aninjection of the alloplastic injectable suspension for use as a dermalfiller comprising A/M copolymer powder (or non-porous microbeads ormicrospheres) and a buffered physiological solution.

Within four weeks to four months of the last injection of the suspendedA/M copolymer the skin comprising the respective nasolabial fold will beraised to the same level as the surrounding skin, such that theappearance of the previously existing nasolabial fold will be diminishedor eliminated. The decrease of appearance or removal of the nasolabialfolds is expected to be permanent, such as to last at least 18 monthswith no palpability or visibility, and from about five to about tenyears. Muscle movement over a time period of from about five to aboutten years may cause the injected A/M copolymer to deepen by 1/10 of amillimeter. If a nasolabial fold glabellar appears during this time, aninjection of the suspended A/M copolymer is placed on top of theoriginal (or last, if more than one were injected) injection of powder,microbeads or microspheres, followed by a second treatment three to fourmonths after the first repeat treatment.

EXAMPLE 4 Reduction of Depressed (“Rolling”) Acne Scars

Twenty patients presenting with either shallow, mildly depressed or deep“rolling” scars, such as having smooth edges which appear similar to“rolling hills,” or “boxcar” scars, such as having a cross-section akinto a box car, are treated by injection of alloplastic injectablesuspension for use as a dermal filler comprising acrylate/methacrylate(A/M) copolymer powder (or non-porous microbeads or microspheres) and abuffered physiological solution (or cross-linked sodium hyaluronate,non-crosslinked sodium hyaluronate or collagen), in accordance with theprocedure described in Example 1, except that the treatment of the“rolling” acne scars is by injection of the suspension of the A/Mcopolymer from a distance of 5 to 10 mm, such as such distance away fromthe scar, and treatment of “boxcar” acne scars is by injection of thesuspension of the A/M copolymer perpendicularly downward into the centerof the scar.

The suspension of the A/M copolymer is implanted as superficially aspossible because blanching of the darkened scars is desired. Blanchingmay be achieved by moving the injected suspension of the A/M copolymerwith the fingernail.

Fresh scars should never be treated because treatment will beineffective and the scar may exacerbated.

Scars which appear to look like “ice picks” may be treated as theaforementioned scars, but must be pre-treated before injection of thesuspension of the A/M copolymer. Pre-treatment may involve punching andsuturing or subcising with an appropriate blade or needle at a depth ofabout 1 mm. In contrast to the “rolling” and “boxcar” scars, thuslypretreated “ice pick” scars are filled with the suspension of the A/Mcopolymer within 3 to 8 days of pre-treatment upon decreased swellingand firm closing of the incision wound.

An injection of less than 0.1 cc of the suspended A/M copolymer willsuffice to treat an acne scar. Acne scars may require a second treatmentwith an injection of the alloplastic injectable suspension for use as adermal filler comprising A/M copolymer powder (or non-porous microbeadsor microspheres) and a buffered physiological solution (or cross-linkedsodium hyaluronate, non-crosslinked sodium hyaluronate or collagen) mayachieve blanching of the scar in addition to the volume fill.

Within four weeks to four months of the last injection of the suspendedA/M copolymer the skin comprising the respective acne scar will beraised to the same level as the surrounding skin, such that theappearance of the previously existing acne scar will be diminished oreliminated. The decrease of appearance or removal of the acne scar isexpected to be permanent, such as to last at least 18 months with nopalpability or visibility, and from about five to about ten years. Ifacne scars re-appear as darkened areas of the skin with a depression ofthe skin of at least a shallow rolling scar, the scar is treated with aninjection of the suspended A/M copolymer, administered in the samemanner as described above for the respective type of acne scar andplaced on top of the original (or last, if more than one were injected)injection of powder, microbeads or microspheres. If the recurringappearance of the scar is not aesthetically pleasing, a second treatmentof the reappeared scar, may follow three to four months after the firstrepeat treatment.

EXAMPLE 6 Reduction of Surgical Scars or Trauma Scars

Twenty patients presenting with either shallow, mildly depressed or deepsurgery scars or trauma scars, for example, from a cut with a sharpobject, either accidental or self-inflicted, are treated by injection ofalloplastic injectable suspension for use as a dermal filler comprisingacrylate/methacrylate (A/M) copolymer powder (or non-porous microbeadsor microspheres) and a buffered physiological solution (or cross-linkedsodium hyaluronate, non-crosslinked sodium hyaluronate or collagen), asthe site of the surgery scars or trauma scars in accordance with theprocedure described in Example 1. Deeper injection site such assubcutaneous tissue and periostial tissue may be needed, depending onthe severity of the scar. Larger amounts of the suspension will beneeded to ameliorate the cosmetic deformities in these cases. Thesecases may require more injections than wrinkles to titrate the desiredeffect.

An injection of 0.1 cc or more of the suspended A/M copolymer willsuffice to treat a surgical scar or trauma scar. Such scars, especiallydeep ones, may require a second treatment with an injection of thealloplastic injectable suspension for use as a dermal filler comprisingA/M copolymer powder (or non-porous microbeads or microspheres) and abuffered physiological solution to achieve filling (and possibleblanching) of the scar.

Within four weeks to four months of the last injection of the suspendedA/M copolymer the skin comprising the surgical scar or trauma scar willbe raised to the same level as the surrounding skin, such that theappearance of the previously existing surgical scar or trauma scar willbe diminished or eliminated. The decrease of appearance or removal ofthe surgical scar or trauma scar is expected to be permanent, such as tolast at least 18 months with no palpability or visibility, and fromabout five to about ten years. If a surgical scar or trauma scarre-appears, the scar is treated with an injection of the suspended A/Mcopolymer, administered in the same manner as described above for theinitial treatment and is placed on top of the original (or last, if morethan one were injected) injection of powder, microbeads or microspheres.If the recurring appearance of the scar is not aesthetically pleasing, asecond treatment of the reappeared scar, may follow three to four monthsafter the first repeat treatment.

EXAMPLE 6 Reduction of Single Crow's Feet

Twenty patients presenting with single crow's feet (one on each sides,but not multiple crow's feet) are treated by injection of alloplasticinjectable suspension for use as a dermal filler comprisingacrylate/methacrylate (A/M) copolymer powder (or non-porous microbeadsor microspheres) and a buffered physiological solution (or cross-linkedsodium hyaluronate, non-crosslinked sodium hyaluronate or collagen), asthe site of the single crow's feet in accordance with the proceduredescribed in Example 1. The area where crow's feet form has thinnerepidermis and dermis. Therefore, a smaller amount of the alloplasticinjectable suspension may be injected.

An injection of 0.05 cc to 0.2 cc of the suspended A/M copolymer willsuffice to treat a single crow's feet Deep single crow's feet mayrequire a second treatment with an injection of the alloplasticinjectable suspension for use as a dermal filler comprising A/Mcopolymer powder (or non-porous microbeads or microspheres) and abuffered physiological solution to achieve filling of the single crow'sfeet.

Within four weeks to four months of the last injection of the suspendedA/M copolymer the skin comprising the single crow's feet will be raisedto the same level as the surrounding skin, such that the appearance ofthe previously existing single crow's feet will be diminished oreliminated. The decrease of appearance or removal of the single crow'sfeet is expected to be permanent, such as to last at least 18 monthswith no palpability or visibility, and from about five to about tenyears. If a single crow's feet re-appears, as a result of musclemovement over time, the single crow's feet is treated with an injectionof the suspended A/M copolymer, administered in the same manner asdescribed above for the initial treatment and is placed on top of theoriginal (or last, if more than one were injected) injection of powder,microbeads or microspheres. If the recurring appearance of the singlecrow's feet is not aesthetically pleasing, a second treatment of thereappeared scar, may follow three to four months after the first repeattreatment.

EXAMPLE 7 Treatment of Other Skin Defects and Medical Conditions

Skin defects besides the aforementioned conditions are treated inaccordance with the procedures described in Example 1 and modified, asneeded, by one of skill, to effect the desired treatment.

The described method of treatment may be used for deformities thatrequire re-contouring such as of a small tissue defect (e.g., afteranimal bite(s)), deformities related to trauma where the deformity iscosmetically unappealing, or for augmentation after plastic surgery toachieve symmetry or a desired result.

Although the invention has been described with reference to variousembodiments and examples, those skilled in the art recognize thatvarious modifications may be made to the invention without departingfrom the spirit and scope thereof

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification areincorporated herein by reference, in their entirety.

What is claimed is:
 1. A method for reducing wrinkles or scarscomprising injecting a dermal filler below the skin at a junction of thedermis and subcutaneous fat, wherein said dermal filler comprises abiocompatible and pliable material and a physiologically acceptablesuspending agent, wherein said biocompatible and pliable material is acopolymer of an unsubstituted acrylate monomer and a substitutedacrylate monomer, wherein the biocompatible and pliable materialcomprises particles having a diameter of less than about 100 μ.
 2. Themethod of claim 1, wherein the substituted acrylate monomer issubstituted with a methyl group.
 3. The method of claim 1, wherein thesubstituted acrylate monomer is substituted with a hydrocarbon chain oftwo, three, four or five carbons.
 4. The method of claim 1, wherein thesubstituted acrylate monomer is substituted with a halogen group.
 5. Themethod of claim 1, wherein the substituted acrylate monomer issubstituted with a nitrile group.
 6. The method of claim 1, wherein thebiocompatible and pliable material is an acrylate/methacrylatecopolymer.
 7. The method of claim 1, wherein the acrylate/methacrylatecopolymer is a solid.
 8. The method of claim 7, wherein the solid is apowder.
 9. The method of claim 8, wherein the solid is a non-porousmicrobead.
 10. The method of claim 8, wherein the solid is amicrosphere.
 11. The method of claim 8, wherein the solid has a diameterof about 10 μ to about 100 μ.
 12. The method of claim 8, wherein thesolid has a diameter of about 0.01 μ to about 10 μ.
 13. The method ofclaim 8, wherein the physiologically acceptable suspending agent isresorbable.
 14. The method of claim 13, wherein the physiologicallyacceptable suspending agent is a buffered physiological solution. 15.The method of claim 13, wherein the physiologically acceptablesuspending agent comprises cross-linked sodium hyaluronate.
 16. Themethod of claim 13, wherein the physiologically acceptable suspendingagent comprises a non cross-linked sodium hyaluronate.
 17. The method ofclaim 13, wherein the physiologically acceptable suspending agentcomprises collagen.
 18. The method of claim 1, wherein said methodfurther comprising administering a local anesthetic.
 19. The method ofclaim 1, said method comprising stimulating collagen production,fibroblast production, fibrocyte production or production of anycombination thereof, beneath the wrinkle or scar.
 20. The method ofclaim 1, wherein the wrinkle or scar is a result of loss of collagen andhyaluronic acid in the skin during the aging process.
 21. The method ofclaim 20, wherein the long-term reduction of the wrinkle or scar is of aduration of at least one year.
 22. A method for reducing horizontalforehead lines, creases, or wrinkles comprising injecting a dermalfiller below the skin at a junction of the dermis and subcutaneous fatproximal to the horizontal forehead lines, creases, or wrinkles, whereinsaid dermal filler comprises a biocompatible and pliable material and aphysiologically acceptable suspending agent, wherein said biocompatibleand pliable material is a copolymer of an unsubstituted acrylate monomerand a substituted acrylate monomer, wherein the biocompatible andpliable material comprises particles having a diameter of less thanabout 100 μ.
 23. A method for reducing glabellar frown lines comprisinginjecting a dermal filler below the skin at a junction of the dermis andsubcutaneous fat at the site of the glabellar frown lines, wherein saiddermal filler comprises a biocompatible and pliable material and aphysiologically acceptable suspending agent, wherein said biocompatibleand pliable material is a copolymer of an unsubstituted acrylate monomerand a substituted acrylate monomer, wherein the biocompatible andpliable material comprises particles having a diameter of less thanabout 100 μ.
 24. A method for reducing nasolabilal folds comprisinginjecting a dermal filler below the skin at a junction of the dermis andsubcutaneous fat at the site of the nasolabilal folds, wherein saiddermal filler comprises a biocompatible and pliable material and aphysiologically acceptable suspending agent, wherein said biocompatibleand pliable material is a copolymer of an unsubstituted acrylate monomerand a substituted acrylate monomer, wherein the biocompatible andpliable material comprises particles having a diameter of less thanabout 100 μ.